期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 13, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI139570
关键词
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资金
- National Institutes of Health, National Heart, Lung, and Blood Institute [K01 HL133530, P01HL151433-01, HL139947]
- National Institute of Neurological Disorders and Stroke [P01 NS092521]
- Be Brave for Life Foundation
- Future Faculty of Cardiovascular Sciences (FOCUS) PRIDE program
- UCSD School of Medicine Microscopy Core [P30 NS047101]
Proliferative astrocytes play a critical role in the pathogenesis of CCM by being a major source of VEGF; non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development; components of the hypoxic program represent potential therapeutic targets for CCMs.
Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2-and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1 alpha in astrocytes, resulting in increased VEGF production and expression of a hypoxic program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1 alpha target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.
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